A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea. Apesar de relativa alta prevalência, possui poucas informações referentes ao perfil cognitivo de seus portadores. Em literatura atual seus portadores são descritos com moderado prejuízo na cognição social em termos de reconhecimento das emoções e expressão do afeto, além de variável nível de inteligência. Em virtude da raridade de pesquisas na área psicológica acerca desta síndrome e, tomando por base recentes estudos, o presente estudo buscou esclarecer o perfil cognitivo de portadores da síndrome de Noonan decorrente de mutação do gene PTPN11, visando a contribuir para o estabelecimento de seu fenótipo comportamental. Foram estudadas 19 pessoas com a síndrome, de ambos os sexos, diagnosticadas clínica e laboratorialmente. A avaliação psicológica foi realizada por meio das escalas Wechsler de inteligência, pelo teste Figuras Complexas de Rey e pelo Teste Wisconsin de Classificação de Cartas. Os resultados obtidos indicaram uma variação entre inteligência normal a retardo mental leve, além de inflexibilidade mental e resposta não adaptada ao feedback ambiental. A avaliação aferiu presença de prejuízos em categorização e, ainda, falha no planejamento do ato motor (praxia) como responsável pelos escores rebaixados em memória episódica visuo-construtiva gráfica. Estes resultados sugerem a necessidade de ampliação de estudos que correlacionem aspectos cognitivos nas mais variadas patologias genéticas / Noonan syndrome is an autosomal dominant genetically heterogeneous disorder. Although relatively high prevalence, there are few information about the cognitive profile of people with the syndorme. Current literature describes moderately impaired social cognition in terms of emotion recognition and emotion affection, besides a variable level of intelligence. Because of rarely researches about psychological area in this syndrome and, based on recent studies, the present study looked for clarify the cognitive profile of people with Noonan syndrome with mutation in the PTPN11 gene, trying to contribute for the establishment of a phenotypic behavior. 19 persons with the syndrome were studied, both male and female, diagnosticaded clinical and laboratorilly. Psychological assessment was realized by using Wechsler intelligence Scales, Rey Complex Figure Test and Wisconsin Card Sorting Test. The results indicated a variation of normal intelligence to mild mental retardation, besides inflexibility and not adapted responses using environmental feedback. The assessment checked the presence of lacked in categories achieved and, even, fault in planning of motor act (praxis) as responsible for low scores in graphic visuoconstruction episodic memory. These results suggest the necessity of expansion of studies which correlated cognitive aspects in the most variables genetic pathologics

Le diabète de type 2 (DT2) est une maladie qui affecte de plus en plus de personnes à travers le monde et comporte plusieurs complications. Les moyens thérapeutiques actuels sont assez limités, car même s'ils sont efficaces, ils sont associés à d'importants effets secondaires. Ainsi, il est important de trouver de nouvelles cibles thérapeutiques pour améliorer la sensibilité à l'insuline en situation d'obésité ou de diabète. Nous nous intéressons ici à une nouvelle cible potentielle, appelée SHP2, qui est une protéine tyrosine phosphatase impliquée dans la transduction du signal en régulant plusieurs voies canoniques (MAPK, PI3K). Cette protéine est connue pour ses rôles cruciaux dans le développement ainsi que son implication dans le métabolisme glucidique. Cependant, cette dernière fonction est encore assez peu comprise, car l'effet d'une délétion de SHP2 sur la sensibilité à l'insuline est différent suivant les tissus et son rôle global n'est pas connu. Nous utilisons ici un modèle original pour étudier l'impact de SHP2 sur le métabolisme glucidique au niveau du corps entier, en travaillant sur le syndrome de Noonan (SN). En effet, cette maladie génétique est principalement causée par une mutation hyperactivatrice du gène PTPN11 codant la protéine SHP2. L'étude du métabolisme glucidique dans le contexte du SN a permis de mettre en évidence une intolérance au glucose, qui est dissociée de l'adiposité réduite, à la fois chez les patients et dans le modèle murin de la maladie (SHP2D61G/+). Nous montrons que les souris SN présentent une inflammation caractérisée par une surexpression de marqueurs pro-inflammatoires, ainsi qu'une augmentation de macrophages pro-inflammatoires dans les tissus métaboliques. [...] / Type 2 diabetes (T2D) is a disease that affects more and more people worldwide and has many severe, lifethreatening complications. The current therapies are rather limited, because even if they are effective, they are associated with significant side effects. Thus, it is important to find new therapeutic targets to improve insulin sensitivity in obesity or diabetes. We are interested here in a new potential target called SHP2, a protein tyrosine phosphatase involved in signal transduction by regulating several canonical pathways (MAPK, PI3K). This protein is known for its crucial roles in development as well as its involvement in glucidic metabolism. However, this latter function is still poorly understood because the effect of a deletion of SHP2 on insulin sensitivity is different between tissues and its overall role is not known. Here, to study the impact of SHP2 on whole body glucidic metabolism we used Noonan Syndrome (NS) as an original model system. Indeed, this genetic disease is mainly caused by a hyperactivating mutation of the gene PTPN11 encoding the protein SHP2. The study of glucidic metabolism in the context of SN has revealed glucose intolerance, which is dissociated from reduced adiposity, both in patients and in the murine model of the disease (SHP2D61G/+). We show that NS mice exhibit inflammation characterized by overexpression of pro-inflammatory markers, as well as an increase of pro-inflammatory macrophages in metabolic tissues. Thanks to bone marrow transplantation and clodronate treatment, we show this inflammation comes from macrophage and is the cause of the insulin resistance in SN.[...]

Noonan syndrome (NS) is one of several autosomal dominant “RASopathies” caused by mutations in components of the RAS-RAF-MEK-ERK MAPK pathway. Germ line mutations in RAF1 (encoding the serine-threonine kinase for MEK1/2) account for ~3-5% of NS, and unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with hypertrophic cardiomyopathy (HCM). Notably, some NS-associated RAF1 mutations show normal or decreased kinase activity. To explore the pathogenesis of such mutations, I generated “knock-in” mice that express kinase-activating (L613V) or -impaired (D486N) Raf1 mutants, respectively. Knock-in mice expressing the kinase-activated allele Raf1L613V developed typical NS features (short stature, facial dysmorphia, haematological abnormalities), as well as HCM. As expected, agonist-evoked Mek/Erk activation was enhanced in multiple cell types expressing Raf1L613V. Moreover, postnatal Mek inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice, showing that enhanced Mek/Erk activation by Raf1 mutant is critical for evoking NS phenotypes. D486N/+ female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1D486N-expressing cells compared with controls. In both mouse and human cells, RAF1D486N, as well as other kinase-impaired RAF1 mutants, show increased heterodimerization with BRAF, which is necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also require heterodimerization to enhance MEK/ERK activation. Our results suggest that increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations.

A síndrome de Noonan (SN), caracterizada por baixa estatura, aspectos dismórficos e cardiopatia congênita, foi associada ao gene PTPN11. Estudamos o PTPN11 em pacientes com SN, pais de portadores de mutação e crianças com baixa estatura idiopática (BEI) que apresentam estigmas sugestivos da SN, sem critérios suficientes para o diagnóstico. Encontramos mutações missense em heterozigoze no PTPN11 em 42,3% dos pacientes com SN. Não identificamos alterações nos pais de portadores de mutação no PTPN11 com fenótipo normal tampouco em crianças com BEI. A única diferença estatisticamente significante entre os grupos com e sem mutação foi a resposta em longo prazo ao hGH, melhor no grupo sem mutação / Noonan syndrome (NS), characterized by short stature, dysmorphic facial and thoracic features and congenital heart disease, was associated to PTPN11 gene. We studied the PTPN11 in patients with NS, parents of mutation-positive NS patients and idiopathic short stature children with signs related to NS without fulfilling the diagnostic criteria. We found missense mutations in 42.3% of the NS group. Parents of NS mutation-positive patients did not present mutations, nor did children with short stature. The only statistically significant difference between groups with and without mutations was response to long term use of hGH, better on the mutation-negative group

INTRODUÇÃO: A síndrome de Noonan é uma doença autossômica dominante caracterizada por baixa estatura, dismorfismos faciais (hipertelorismo ocular, inclinação para baixo das fendas palpebrais, ptose palpebral, palato alto e má-oclusão dentária), pescoço curto e/ou alado, defeitos cardíacos, principalmente a estenose pulmonar valvar, deformidade esternal e criptorquia nos pacientes do sexo masculino. O gene PTPN11, localizado no braço longo do cromossomo 12 (12q24.1), é responsável por aproximadamente 50% dos casos de síndrome de Noonan. OBJETIVO: Detectar a freqüência de mutações no gene PTPN11 em uma amostra de pacientes os quais preenchiam os critérios clínicos para a síndrome de Noonan e síndromes Noonan-like e estabelecer uma correlação genótipo-fenótipo. MÉTODOS: Cinqüenta probandos com síndrome de Noonan, 3 com síndrome de LEOPARD, 3 com síndrome de Noonan-like/lesões múltiplas de células gigantes e 2 com neurofibromatose-Noonan foram incluídos nesse estudo. O estudo molecular foi realizado através da técnica da cromatografia líquida de alta precisão desnaturante e, naqueles com um perfil anormal, a técnica do seqüenciamento do éxon em questão foi concretizada. RESULTADOS: Mutações missense no gene PTPN11 foram identificadas em 21 probandos com síndrome de Noonan (42%), em todos os três pacientes com a síndrome de LEOPARD, em um caso com síndrome de Noonan-like/lesões múltiplas de células gigantes e em um paciente com síndrome da neurofibromatose-Noonan. Este último probando também apresentava uma mutação no gene NF1. A única anomalia que atingiu uma diferença estatisticamente significante quando comparados os grupos de pacientes com e sem mutação foi o grupo de distúrbios hematológicos. Um paciente com síndrome de Noonan que apresentou uma doença mieloproliferativa possuía a mutação T73I. CONCLUSÃO: A síndrome de Noonan é uma doença heterogênea, uma vez que mutações no gene PTPN11 são responsáveis por 42% dos casos. Uma correlação genótipo-fenótipo definitiva não foi estabelecida, mas a mutação T73I parece predispor a distúrbios mieloproliferativos. Com relação às síndromes Noonan-like, o gene PTPN11 é o principal responsável pela síndrome de LEOPARD e também desempenha um papel na síndrome da neurofibromatose-Noonan. A síndrome de Noonan-like/lesões múltiplas de células gigantes, a qual faz parte do espectro da síndrome de Noonan, é também uma doença heterogênea. / INTRODUCTION: Noonan syndrome is an autosomal dominant disorder comprising short stature, facial dysmorphisms (ocular hypertelorism, downslanting palpebral fissures, palpebral ptosis, high arched palate and dental malocclusion), short and/or webbed neck, heart defects, mainly valvar pulmonary stenosis, sternal deformity and cryptorchidism in males. The PTPN11 gene, localized in the long arm of chromosome 12 (12q24.1), is responsible for approximately 50% of the cases. OBJECTIVE: To detect the PTPN11 gene mutation rate in a cohort of clinically well-characterized patients with Noonan and Noonan-like syndromes and to study the genotype-phenotype correlation. METHODS: Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 3 with Noonan-like/multiple giant cell lesion syndrome and 2 with neurofibromatosis/Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography followed by sequencing of amplicons with an aberrant elution profile. RESULTS: Missense mutations in the PTPN11 gene were identified in 21 probands with Noonan syndrome (42%), in all three patients with LEOPARD syndrome, in one case with Noonan-like/multiple giant cell lesion syndrome and in one with neurofibromatosis-Noonan syndrome. This last patient also showed a NF1 gene mutation. The only anomaly that reached statistical significance when comparing probands with and without mutations was the hematological abnormalities. A Noonan syndrome patient presenting a myeloproliferative disorder showed a T73I mutation. CONCLUSION: Noonan syndrome is a heterogeneous disorder, once PTPN11 gene mutations is responsible for 42% of the cases. A definitive genotype-phenotype correlation is not established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, the PTPN11 gene is the main one in LEOPARD syndrome and also plays a role in neurofibromatosis-Noonan syndrome. Noonan-like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.

INTRODUÇÃO: A síndrome de Noonan é uma doença autossômica dominante caracterizada por baixa estatura, dismorfismos faciais (hipertelorismo ocular, inclinação para baixo das fendas palpebrais, ptose palpebral, palato alto e má-oclusão dentária), pescoço curto e/ou alado, defeitos cardíacos, principalmente a estenose pulmonar valvar, deformidade esternal e criptorquia nos pacientes do sexo masculino. O gene PTPN11, localizado no braço longo do cromossomo 12 (12q24.1), é responsável por aproximadamente 50% dos casos de síndrome de Noonan. OBJETIVO: Detectar a freqüência de mutações no gene PTPN11 em uma amostra de pacientes os quais preenchiam os critérios clínicos para a síndrome de Noonan e síndromes Noonan-like e estabelecer uma correlação genótipo-fenótipo. MÉTODOS: Cinqüenta probandos com síndrome de Noonan, 3 com síndrome de LEOPARD, 3 com síndrome de Noonan-like/lesões múltiplas de células gigantes e 2 com neurofibromatose-Noonan foram incluídos nesse estudo. O estudo molecular foi realizado através da técnica da cromatografia líquida de alta precisão desnaturante e, naqueles com um perfil anormal, a técnica do seqüenciamento do éxon em questão foi concretizada. RESULTADOS: Mutações missense no gene PTPN11 foram identificadas em 21 probandos com síndrome de Noonan (42%), em todos os três pacientes com a síndrome de LEOPARD, em um caso com síndrome de Noonan-like/lesões múltiplas de células gigantes e em um paciente com síndrome da neurofibromatose-Noonan. Este último probando também apresentava uma mutação no gene NF1. A única anomalia que atingiu uma diferença estatisticamente significante quando comparados os grupos de pacientes com e sem mutação foi o grupo de distúrbios hematológicos. Um paciente com síndrome de Noonan que apresentou uma doença mieloproliferativa possuía a mutação T73I. CONCLUSÃO: A síndrome de Noonan é uma doença heterogênea, uma vez que mutações no gene PTPN11 são responsáveis por 42% dos casos. Uma correlação genótipo-fenótipo definitiva não foi estabelecida, mas a mutação T73I parece predispor a distúrbios mieloproliferativos. Com relação às síndromes Noonan-like, o gene PTPN11 é o principal responsável pela síndrome de LEOPARD e também desempenha um papel na síndrome da neurofibromatose-Noonan. A síndrome de Noonan-like/lesões múltiplas de células gigantes, a qual faz parte do espectro da síndrome de Noonan, é também uma doença heterogênea. / INTRODUCTION: Noonan syndrome is an autosomal dominant disorder comprising short stature, facial dysmorphisms (ocular hypertelorism, downslanting palpebral fissures, palpebral ptosis, high arched palate and dental malocclusion), short and/or webbed neck, heart defects, mainly valvar pulmonary stenosis, sternal deformity and cryptorchidism in males. The PTPN11 gene, localized in the long arm of chromosome 12 (12q24.1), is responsible for approximately 50% of the cases. OBJECTIVE: To detect the PTPN11 gene mutation rate in a cohort of clinically well-characterized patients with Noonan and Noonan-like syndromes and to study the genotype-phenotype correlation. METHODS: Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 3 with Noonan-like/multiple giant cell lesion syndrome and 2 with neurofibromatosis/Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography followed by sequencing of amplicons with an aberrant elution profile. RESULTS: Missense mutations in the PTPN11 gene were identified in 21 probands with Noonan syndrome (42%), in all three patients with LEOPARD syndrome, in one case with Noonan-like/multiple giant cell lesion syndrome and in one with neurofibromatosis-Noonan syndrome. This last patient also showed a NF1 gene mutation. The only anomaly that reached statistical significance when comparing probands with and without mutations was the hematological abnormalities. A Noonan syndrome patient presenting a myeloproliferative disorder showed a T73I mutation. CONCLUSION: Noonan syndrome is a heterogeneous disorder, once PTPN11 gene mutations is responsible for 42% of the cases. A definitive genotype-phenotype correlation is not established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, the PTPN11 gene is the main one in LEOPARD syndrome and also plays a role in neurofibromatosis-Noonan syndrome. Noonan-like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.

Noonan syndrome (NS) is one of several autosomal dominant “RASopathies” caused by mutations in components of the RAS-RAF-MEK-ERK MAPK pathway. Germ line mutations in RAF1 (encoding the serine-threonine kinase for MEK1/2) account for ~3-5% of NS, and unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with hypertrophic cardiomyopathy (HCM). Notably, some NS-associated RAF1 mutations show normal or decreased kinase activity. To explore the pathogenesis of such mutations, I generated “knock-in” mice that express kinase-activating (L613V) or -impaired (D486N) Raf1 mutants, respectively. Knock-in mice expressing the kinase-activated allele Raf1L613V developed typical NS features (short stature, facial dysmorphia, haematological abnormalities), as well as HCM. As expected, agonist-evoked Mek/Erk activation was enhanced in multiple cell types expressing Raf1L613V. Moreover, postnatal Mek inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice, showing that enhanced Mek/Erk activation by Raf1 mutant is critical for evoking NS phenotypes. D486N/+ female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1D486N-expressing cells compared with controls. In both mouse and human cells, RAF1D486N, as well as other kinase-impaired RAF1 mutants, show increased heterodimerization with BRAF, which is necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also require heterodimerization to enhance MEK/ERK activation. Our results suggest that increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations.

A síndrome de Noonan (SN), caracterizada por baixa estatura, aspectos dismórficos e cardiopatia congênita, foi associada ao gene PTPN11. Estudamos o PTPN11 em pacientes com SN, pais de portadores de mutação e crianças com baixa estatura idiopática (BEI) que apresentam estigmas sugestivos da SN, sem critérios suficientes para o diagnóstico. Encontramos mutações missense em heterozigoze no PTPN11 em 42,3% dos pacientes com SN. Não identificamos alterações nos pais de portadores de mutação no PTPN11 com fenótipo normal tampouco em crianças com BEI. A única diferença estatisticamente significante entre os grupos com e sem mutação foi a resposta em longo prazo ao hGH, melhor no grupo sem mutação / Noonan syndrome (NS), characterized by short stature, dysmorphic facial and thoracic features and congenital heart disease, was associated to PTPN11 gene. We studied the PTPN11 in patients with NS, parents of mutation-positive NS patients and idiopathic short stature children with signs related to NS without fulfilling the diagnostic criteria. We found missense mutations in 42.3% of the NS group. Parents of NS mutation-positive patients did not present mutations, nor did children with short stature. The only statistically significant difference between groups with and without mutations was response to long term use of hGH, better on the mutation-negative group

SPRED 2 wirkt inhibitorisch auf den Ras/ERK-MAPK-Signalweg. Im Knockout Mausmodell zeigen sich einige schwerwiegende phänotypische Eigenschaften, unter anderem zeigen sich ein genereller Minderwuchs, veränderte hormonelle Regelkreise, neurologische Auffälligkeiten, eine deutlich verringerte Lebenserwartung, sowie kardiale Veränderungen. Besonders schwerwiegende SPRED 2 KO typische Ausprägungen im Herzen sind hierbei eine myokardiale Fibrosierung, eine myokardiale Hypertrophie und Herzrhythmusstörungen. In dieser Arbeit wurden insbesondere kardiale Veränderungen auf Zell- und Proteinebene untersucht. Zur Proteinanalyse der Kardiomyozyten wurden Western Blots und eine Schnittbildgebung angefertigt. Für eine funktionelle Untersuchung wurden isolierte vitale Kardiomyozyten mittels Fluoreszenzfarbstoffen untersucht und unter elektrischer Stimulation beobachtet. Desweiteren wurden isolierte Mitochondrien auf ihren Stoffwechsel und eventuelle Defekte hin analysiert. Hierbei konnte gezeigt werden, dass junge SPRED2 KO Mäuse keine wesentlichen hämodynamischen Einschränkungen aufweisen und eine gute Kompensationsfähigkeit gegenüber einer Nachlaststeigerung aufweisen. Auch gezeigt werden konnte, dass Veränderungen im Rahmen der Zellkontraktion beim Kalziumhaushalt und Membranpotential existieren und im Zusammenhang mit einer verminderten Expression von SERCA und CaV1.2 stehen. Bei der Untersuchung von Mitochondrien konnten keine wesentlichen Defizite der mitochondrialen Funktion der SPRED 2 KO Mäuse gefunden werden. In diesem Zusammenhang ist die bekannte Störung der Autophagie am ehesten Ursache für eine gesteigerte Fibrosierung, sowie der gesteigerten Apoptose der Kardiomyozyten. In Folge dessen könnten die oben beschriebenen Veränderungen des Kalziumhaushaltes der Kardiomyozyten stehen und letztendlich über maligne Herzrhythmusstörungen zum vorzeitigen Versterben führen. / SPRED 2 has an inhibitory effect on the Ras/ERK-MAPK signaling pathway. In the knockout mouse model, some severe phenotypic features are shown, among others a general short stature, altered hormonal regulatory circuits, neurological abnormalities, a significantly reduced life expectancy, and cardiac changes. Especially severe SPRED 2 KO typical manifestations in the heart are myocardial fibrosis, myocardial hypertrophy and cardiac arrhythmias. In this work, cardiac changes at the cellular and protein levels were studied in particular. For protein analysis of the cardiomyocytes, Western blots and cross-sectional imaging were performed. For a functional study, isolated vital cardiomyocytes were examined by fluorescent dyes and observed under electrical stimulation. Furthermore, isolated mitochondria were analyzed for metabolism and possible defects. It was shown that young SPRED2 KO mice do not exhibit significant hemodynamic limitations and show a good ability to compensate for the increase in afterload. Moreover, it was shown that alterations in cell contraction exist in calcium balance and membrane potential and are associated with decreased expression of SERCA and CaV1.2. When mitochondria were examined, no significant deficits in mitochondrial function were found in SPRED 2 KO mice. In this context, the known disruption of autophagy is most likely the cause of increased fibrosis, as well as increased apoptosis of cardiomyocytes. As a consequence, the above calcium balance of the cardiomyocytes ultimately lead to premature death via malignant cardiac arrhythmias.

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